Synthesis and anticonvulsant activity of novel and potent 6,7-methylenedioxyphthalazin-1(2H)-ones

In this paper, we describe the synthesis of a series of novel substituted 4 -aryl-6,7-methylenedioxyphthalazin-1(2H)-ones. The anticonvulsant activity of these compounds against audiogenic seizures was evaluated in DBA/2 mice after intraperitoneal (ip) injection. Most of these derivatives are more ac tive than 1-(4-aminophenyl)-4-methyl-7,8-methylene,2,3-benzodiazepine (1, G YKI 52466), a well-known noncompetitive AMPA receptor antagonist. As deduce d by the rotarod test, all the compounds exhibit a toxicity lower than that of 1. Within the series of derivatives submitted to investigation, 4-(4-am inophenyl)-2-butylcarbamoyl-6,7-methylenedioxyphthalazin-1(2H)-one (21) pro ved to be the most active compound and is 11-fold more potent than 1 (i.e., ED50 3.25 mu mol/kg for 21 versus ED50 35.8 mu mol/kg for 1). When compare d to 1, compound 21 as well as its analogue 4-(4-aminophenyl)-6,7-methylene dioxyphthalazin-1(2H)-one (16) show a longer lasting anticonvulsant activit y. Compound 21 also effectively suppresses seizures induced in Swiss mice b y maximal electroshock (MES) and pentylenetetrazole (PTZ). Furthermore, it antagonizes in vivo seizures induced by 2-amino-3-(3-hydroxy-5-methylisoxaz ol-4-yl)propionic acid (AMPA), 2-amino-3-(3-hydroxy-5-tert-butyl-isoxazol-4 -yl)propionic acid (ATPA), and kainate (KA), and its anticonvulsant activit y is reversed by pretreatment with aniracetam. Using the patch-clamp techni que, the capability of derivatives 16 and 21 to antagonize KA-evoked curren ts in primary cultures of granule neurons was tested. They behaved as antag onists, but they proved to be less effective than 1 and 1-(4-aminophenyl)-3 , 4-dihydro-4-methyl-3-N-methylcarbamoyl-7, 8-methylenedioxy-5H-2,3-benzodi azepine (2, GYKI 53655) to reduce the KA-evoked currents.